Author + information
- Received September 10, 2011
- Revision received January 13, 2012
- Accepted February 29, 2012
- Published online September 1, 2012.
- Maysoon Elkhawad, MBBChir, MA⁎,†,
- James H.F. Rudd, MBChB, PhD†,
- Lea Sarov-Blat, PhD‡,
- Gengqian Cai, PhD‡,
- Richard Wells, BA⁎,
- L. Ceri Davies, MD, MBBS§,
- David J. Collier, PhD, MBBS§,
- Michael S. Marber, MBBS, PhD∥,
- Robin P. Choudhury, BMBCh, MA, DM¶,
- Zahi A. Fayad, PhD#,
- Ahmed Tawakol, MD⁎⁎,
- Fergus V. Gleeson, MBBS¶,
- John J. Lepore, MD‡,
- Bill Davis, PhD††,
- Robert N. Willette, PhD‡,
- Ian B. Wilkinson, BMBCh, DM⁎,
- Dennis L. Sprecher, MD‡,⁎ ( and )
- Joseph Cheriyan, MBChB⁎,††,‡‡
- ↵⁎Reprint requests and correspondence:
Dr. Dennis Sprecher, GlaxoSmithKline, 709 Swedeland Road, UW2421, King of Prussia, Pennsylvania 19406
Objectives This study sought to determine the effects of a p38 mitogen-activated protein kinase inhibitor, losmapimod, on vascular inflammation, by 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography imaging.
Background The p38 mitogen-activated protein kinase cascade plays an important role in the initiation and progression of inflammatory diseases, including atherosclerosis.
Methods Patients with atherosclerosis on stable statin therapy (n = 99) were randomized to receive losmapimod 7.5 mg once daily (lower dose [LD]), twice daily (higher dose [HD]) or placebo for 84 days. Vascular inflammation was assessed by FDG positron emission tomography/computed tomography imaging of the carotid arteries and aorta; analyses focused on the index vessel (the artery with the highest average maximum tissue-to-background ratio [TBR] at baseline). Serum inflammatory biomarkers and FDG uptake in visceral and subcutaneous fat were also measured.
Results The primary endpoint, change from baseline in average TBR across all segments in the index vessel, was not significantly different between HD and placebo (ΔTBR: −0.04 [95% confidence interval [CI]: −0.14 to +0.06], p = 0.452) or LD and placebo (ΔTBR: −0.02 [95% CI: −0.11 to +0.06], p = 0.579). However, there was a statistically significant reduction in average TBR in active segments (TBR ≥1.6) (HD vs. placebo: ΔTBR: −0.10 [95% CI: −0.19 to −0.02], p = 0.0125; LD vs. placebo: ΔTBR: −0.10 [95% CI: −0.18 to −0.02], p = 0.0194). The probability of a segment being active was also significantly reduced for HD when compared with placebo (OR: 0.57 [95% CI: 0.41 to 0.81], p = 0.002). Within the HD group, reductions were observed in placebo-corrected inflammatory biomarkers including high-sensitivity C-reactive protein (% reduction: −28% [95% CI: −46 to −5], p = 0.023) as well as FDG uptake in visceral fat (ΔSUV: −0.05 [95% CI: −0.09 to −0.01], p = 0.018), but not subcutaneous fat.
Conclusions Despite nonsignificant changes for the primary endpoint of average vessel TBR, HD losmapimod reduced vascular inflammation in the most inflamed regions, concurrent with a reduction in inflammatory biomarkers and FDG uptake in visceral fat. These results suggest a systemic anti-inflammatory effect. (A Study to Evaluate the Effects of 3 Months Dosing With GW856553, as Assessed FDG-PET/CT Imaging; NCT00633022)
- p38 mitogen-activated protein kinase inhibition
- randomized controlled trial
This study was funded by GlaxoSmithKline. Ms. Elkhawad, and Drs. Rudd, Wilkinson, and Cheriyan, as well as the Cambridge University Hospitals PET/CT Unit, have received funding support from National Institute for Health Research (NIHR) Cambridge Comprehensive Biomedical Research Centre. Ms. Elkhawad has received funding support from the Raymond and Beverly Sackler Foundation. Drs. Rudd and Wilkinson are consultants for GlaxoSmithKline. Drs. Sarov-Blat, Cai, Lepore, Davis, Willette, and Sprecher are employees of and own stock in GlaxoSmithKline. Mr. Wells has reported that he has no relationships relevant to the contents of this paper to disclose. Drs. Davies and Collier have received funding from NIHR Cardiovascular Biomedical Research Unit, Bart's and the London School of Medicine and Dentistry. Dr. Collier has received a research grant from GlaxoSmithKline for this study. Dr. Marber has received funding from the NIHR Comprehensive Biomedical Research Centre, Guy's and St Thomas's National Health Service Foundation Trust in partnership with the British Heart Foundation Centre, King's College, London. He has received a research grant from and is a consultant for GlaxoSmithKline for this compound. Drs. Choudhury and Gleeson have received funding from the NIHR Oxford Comprehensive Biomedical Research Centre. Dr. Choudhury is a Wellcome Trust Senior Research fellow and is supported by the British Heart Foundation Centre for Research Excellence, Oxford. He has received a research grant for this study and is on the advisory board of AstraZeneca and Roche. Dr. Fayad has received research grants from GlaxoSmithKline, AstraZeneca, Roche, Bristol-Myers Squibb Merck & Co. Inc., VBL Therapeutics, Philips, Siemens, Novartis, and the National Institute of Health. Dr. Tawakol has received research grants from Bristol-Myers Squibb, GlaxoSmithKline, Merck & Co. Inc., Genentech/Roche, VBL Therapeutics, Siemens, Novartis, and the National Institute of Health. He consults for Bristol-Myers Squibb, GlaxoSmithKline, Merck & Co. Inc., Novartis, and Roche. Dr. Wilkinson has received funding support from the British Heart Foundation as a funded post holder; he has also received educational grants from GlaxoSmithKline for current clinical trials. Dr. Cheriyan is employed by Cambridge University Hospitals National Health Service Foundation Trust and is obligated to spend 50% of his time on GlaxoSmithKline clinical trial research, representing a significant relationship; however, he receives no other benefits or compensations from GlaxoSmithKline. Ms. Elkhawad and Dr. Rudd contributed equally to this paper. H. William Strauss, MD, served as Guest Editor for this paper.
- Received September 10, 2011.
- Revision received January 13, 2012.
- Accepted February 29, 2012.
- American College of Cardiology Foundation